Preparation of carboxylic acid esters and lactone



Patented Jan. 12, 1943 PREPARATION OF CARBOXYLIC ACID ESTEBS ANDIACTONE Richard Pasternack, Islip, and Bay Arthur Pateiski, Flushing, N. Y., assignors to Charles Pfizer & Company, Brooklyn, N. Y., a corporation of New Jersey -No Drawing. Application January 17, 1942, ScrialNo. 427,112

Claims. 260-4484) This application relates to the preparation of useful monocarboxylic acids by stepwise reduction of the optically active tartaric acids,-and is acontinuation in part of our copending application Serial Number 318,102 U. S. 3 2,277,872. A

particular object of the invention is the prepara tion in a commercially practicable way of the optic'ally active threonic acids and threonolactones,

which are useful in the preparation of vitamin C.

Hitherto threonic' acid and its derivatives have been prepared with difiiculty and only from expensive materials; for example, by alkaline oxidation of arabinose, as in German Patent No. 620,248 (Spengler and Pfannenstiehl, 1934) or by potassium permanganate oxidation of ascorbic acid and subsequent purification of the crude product by distillation under high vacuum (Gatzi and, Reichstein, Helv. Chim. .Acta 20: 1298-1301 of 1937). mixtures diflicult to separate, and yields of the desired products were poor.

Our process uses dor l-tartaric acid and gives almost theoretical yields throughout. By the sucin the preparation of l-threonolacton'e from d-tartaric acid.

The preparation of diacetyltartaric anhydride from tartaric acid was described, for example, by Wohl and Oesterlin (Ber. 34: L144 01 1901), and is not a part of our invention. It is obvious to esterify this anhydride with the aliphatic alcohols, but the diesters are useless for our purpose. We have found, however, that if diacetyltartaric anhydride-is treated at below 100 C. withan anhydrous alcohol, preferably in a dry inert mutual solvent without the addition of any esteriflcation catalyst, the monoester forms in almost quantitative yield. For use in the preparation of the acid chloride the resulting ester need not be isolated.

It is known to convert carboxylic acids into the corresponding acid chlorides by the action of thionyl chloride, phosphorus pentachloride or phosphorus trichloride and chlorine, but in so far as we have been able to determine, this treat ment has not been applied to acylated ester acids. The stabilityof such compounds toward phosphorus pentachloride could not-have been predicted. We have found, however, that under our conditions using temperatures below 100 C.

The oxidation products were often.

each case is a moderately stable acid chloride of the ester of diacetyltartaric acid used. It may be isolated by crystallization, but is not sufficiently stable to be kept for longrperiods even under favorable conditions. Treatment of the monoester of diacetyltartaric acidv with phosphorus pentachloride is best carried out in a chemically inert liquid medium capable of holding the acid chloride product in solution. The selection and amount of solvent are not critical, but xylene has been found very satisfactory, and in any case a.

suflicient volume should be present to form a clear solution of the acid chloride product at the temperature used. I

e acid chlorides of the lower alcohol monoest rsof the diacetyltartaric acids are next reduced by hydrogen according to the general methods of Rosenmund (Ber. 51: 585 of 1918) and Rosenmund and Zetzsche (Ber. 54: 425 and 638 of 1921) for the reduction of acid chlorides. In the complete absence of water, substantially theoretical yields of the corresponding esters of the diacetylthreuronic acids can be obtained. This part of our invention is illustrated by the reduction of the methyl ester of diacetyl-d-tartaric acid chloride by hydrogen using a palladium catalyst.

Loweralcohol esters of the diacetylthreuronic acids are converted to lower alcohol esters of 2,3-diacetylthreonic acids by catalytic hydrogenation. The time required to effect this reduction varies with the pressure of hydrogen used, the

catalyst, and the solvent. We have obtained very satisfactory reduction of the esters in dioxan solution at room temperature, using a Raney nickel "catalyst and hydrogen at 120 atmospheres pressure.

' taric acid. Also, it is not intended that our inventionbe limited by the proportions of materials used in the examples, although almost theoretical yields are obtained by use of the procedures as the substituents are not lost, and the product in 55 given. The following is a structural illustration of the preparation of l-threonolactone from diacetyl-d-tartaric anhydride.

o=c o=c-o on. H-C-O-Acyl H- '-0Acyl Ae i-o-c-nl Acyl-O- -n 0=c- H Diacetyl-d-tartaric acid Monomethyl ester of diacetylanhydride d-tartaric acid O- -C-OC Hs 0=C-OCH1 H-'G0 -Acyl H-c 0-Acyi Acyl-O-C-II licyl-O- -n O=(|JH 0 =C-Cl Methyl ester oidiacetyl- Methyl ester of diacetyl-d-tartaric l-threuronio acid acid chloride o=cocn. o=c n- --OAcyl n-d-on Acyl-O- H HO- H 0 H- OH n- Methyl ester of 2,3'diacetyli-Threonolaetone l-thraonic acid Examples of steps of the process xylene and possessed a melting point of 8847 C.

[a] ='+27.5 (c.1inchloroform) [l" =-22.5 (c, 1 in acetone). It is readily saponined, but we have not been able to crystallize the deacetylated product.

Methyl ester of 2,3-diacetyl-l-threonic acid- A mixture of 232 grams of the methyl ester of diacetyl-l-threuronic acid, 50 g. of Raney nickel and 600 cc. of dioxan was placed in a rocker, bomb-type hydrogenator and subjected to hydrogen at 120 atmospheres pressure. After 12 hours of reaction the catalyst was removed and the crystalline product which resulted when the solvent was evaporated at subatmospheric pressure was recrystallized from xylene; M. P., IQ-81 C. [a]= =25.5 (c, 1 inmethanol); [(l] =-21.5 (c, 1 in acetone).

l-Threonolactone.-A solution of 23.4 grams of the methyl ester of 2,3-diacetyl-l-threonic acid, 5 cc. of 50% sulfuric acid and 200 cc. of water was heated on a steam bath for 3 hours. The sulfuric acid was then removed with barium carbonate. the aqueous solution concentrated at subatmospheric pressure, and the sirupy residue which resulted was heated at l00-105 C. under 0.5-1.0 mm. pressure for 2 hours. (While Gatzi and Reichstein produced threonolactone by distilla- Methyl ester of diacetyl-d-tartaric acid-A mixture 01 216 grams of diacetyl-d-tartaric acid anhydride, 44 cc. of methanol and 250 cc. of dry xylene was refluxed on a steam bath for thirty minutes. The solventswere removed by distillation at subatmospheric pressure, and after recrystallization from acetone the colorless crystalline product melted at 125.5l27 C.

tion under high vacuum, dehydration under high vacuum gives much more satisfactory results, the product being of higher melting point and not contaminated with decomposition products.) The crystalline product which resulted after cooling the residue was washed with acetic acid and then with benzene; M. P., 7476 C. [a]= =+47 (c. 1.5 in methanol).

We claim: I

1. Process for the preparation of acylated aliphatic compounds of the formula cooa HO-Acyl BIO-Acyl mon where R is a lower alinyl group, comprising treating diacylated tartaric anhydride with an anhythe mixture heated on a steam bath until reaction methyl ester of d-tartaric acid chloride, 8 cc. of

acetyl chloride and 600 cc. of dry xylene. The reactionmixture was maintained at 100 110 until the evolution othydrogen chloride had ceased (about 5 hours)", the catalyst removed by filtration and the solution-cooled. The crystalline product obtained was recrystallized from drous lower aliphatic alcohol to form the monoester; treating the monoester at below C.

diacetyltartaric acids, comprising the combination of the following successive steps: formation of a monomethyl ester of one of the aforesaid tartaric acids by treatment with methyl alcohol at below 100 C. in the absence of a catalyst, conversion of the ester to the corresponding acid chloride by the action of a suitable inorganic acid chloride at temperatures below 100 0., reduction of the acid chloride group by hydrogen in the presence of a palladium catalyst to form the methyl ester of the corresponding diacetylthreuronic acid, isolation of this intermediate, and further reduction of the aldehyde group of the aforesaid threuronic acid by hydrogen at elevated pressures and in the presence of a catalyst to form the corresponding threonic acid esterJ complete hydrolysis of the acetylated threonic acid esters, and lactonization of the resultmg threonic acid by dehydration under high (100R vacuum at a temperature above 100 C., but CHO--Acy1 below the distillation point. L

3. In the preparation of threonolactones from v J lower alcohol esters of diacetylthreuronic acid, 5 the step of reducing a lower alcohol ester of where R is a, lower alkyl group. diacetylthreuronic acid with pressure hydrogen 5. As new products, the rhethyl esters of the in the presence of a Raney nickel catalyst. optically active 2,3-diacetylthreonic acids.

4. As new'products, acylated organic com- RICHARD PASTERNACK.

pounclsof the formula I 10 RAY A. PATELSKI. 

